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APC-Associated Polyposis Conditions

, MS, , MD, MS, and , MD.

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Initial Posting: ; Last Update: February 2, 2017.

Summary

Clinical characteristics.

APC-associated polyposis conditions include: familial adenomatous polyposis (FAP), attenuated FAP, and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).

  • FAP is a colon cancer predisposition syndrome in which hundreds to thousands of adenomatous colonic polyps develop, beginning, on average, at age 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include: polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers.
  • Attenuated FAP is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of colon cancer at a later age than in FAP. Certain extracolonic manifestations, such as gastric and duodenal polyps or cancers, are variably present in attenuated FAP; risk management may be substantially different between FAP and attenuated FAP.
  • GAPPS is characterized by gastric fundic gland polyposis, increased risk of gastric cancer, and limited colonic involvement in most individuals reported.

Diagnosis/testing.

The diagnosis of an APC-associated polyposis condition is now established by molecular genetic testing. Typically, it is suspected in an individual with suggestive personal and/or family history features and confirmed by identification of a heterozygous germline pathogenic variant in APC.

Management.

Treatment of manifestations: There is an absolute indication for colectomy when colorectal cancer is diagnosed or suspected, or when there are significant symptoms (bleeding/obstruction). Relative indications for colectomy include presence of multiple adenomas larger than 6 mm that cannot be reasonably removed endoscopically, a significant increase in adenoma number between surveillance exams, presence of adenomas with high-grade dysplasia, or inability to adequately survey the colon (e.g., due to innumerous diminutive adenomas or limited access to/compliance with colonoscopy). Several studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have caused regression of adenomas in FAP and decreased the polyp burden, though there are currently no FDA-approved chemopreventive agents for FAP. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumors may be surgically excised or treated with NSAIDs, anti-estrogens, cytotoxic chemotherapy, and/or radiation.

Surveillance: Colorectal screening beginning at age ten to 12 years for FAP and in late teens for attenuated FAP; esophagogastroduodenoscopy by age 20-30 years or prior to colon surgery; regular physical examinations including thyroid palpation, neurologic examination, and abdominal examination (for desmoids); consider annual thyroid ultrasound imaging for increased risk of thyroid cancer. Consider screening for hepatoblastoma by liver ultrasound and measurement of serum alpha-fetoprotein concentration (until age 5 years). The efficacy of screening for gastric cancer or prophylactic gastrectomy is currently unknown for individuals with GAPPS.

Evaluation of relatives at risk: Molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant.

Genetic counseling.

APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with an APC-associated polyposis condition have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant in APC. Prenatal testing and preimplantation genetic diagnosis are possible if a pathogenic variant has been identified in an affected family member.

GeneReview Scope

APC-Associated Polyposis Conditions: Included Phenotypes
  • Familial adenomatous polyposis
  • Attenuated FAP
  • Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

The National Comprehensive Cancer Network (NCCN) has published an algorithm for consideration of the diagnosis of both FAP and attenuated FAP [Provenzale et al 2016]. These guidelines include recommendations for genetic testing of APC. Consensus guidelines specific for GAPPS are not yet available.

According to the NCCN guidelines, an APC-associated polyposis condition should be suspected in individuals with any of the following clinical features:

  • Multiple colorectal adenomatous polyps (at least 10-20 cumulative colorectal adenomatous polyps)
  • Family history of multiple colorectal adenomatous polyps (>10 in a single individual, or fewer if >1 relative has multiple polyps, especially if diagnosed at a young age) and/or extracolonic features mentioned below. The total number of polyps, age of onset, number of affected relatives, and presence or absence of extracolonic findings may influence if referral for genetic counseling and/or testing is necessary based on family history.
  • Hepatoblastoma
  • Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
  • Desmoid tumor
  • Cribriform-morular variant of papillary thyroid cancer

Additional features suggestive of an APC-associated polyposis condition. The presence of the following additional features may influence the decision to offer APC genetic testing: early-onset colorectal cancer with few to no adenomatous polyps, dental abnormalities (e.g., supernumerary teeth), osteomas, odontomas, epidermoid cysts, duodenal adenomas and cancer, gastric fundic gland polyposis, gastric cancer, pancreatic cancer, small bowel carcinoma, and/or medulloblastoma.

Establishing the Diagnosis

The diagnosis of an APC-associated polyposis condition is typically considered in an individual with characteristic clinical findings and is established by identification of a heterozygous germline pathogenic variant in APC (see Table 1).

Note: A variety of terms have been used to describe individuals with an APC-associated polyposis condition; FAP, attenuated FAP, Gardner syndrome, Turcot syndrome, or the recently described gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). The clinical features associated with these phenotypes are included here; however, all are now genetically defined as caused by pathogenic variants in APC. Terms such as Gardner syndrome and Turcot syndrome are of historical interest and should not be used any longer as both are now known to be part of the FAP spectrum. GAPPS was only recently described and the current phenotype is not yet well understood. Management guidelines differ between FAP and attenuated FAP. A consensus has not been reached regarding the precise clinical diagnostic criteria that distinguish FAP from attenuated FAP.

The diagnosis of familial adenomatous polyposis (FAP) is considered in an individual with a heterozygous germline pathogenic variant in APC by molecular genetic testing (see Table 1) and ONE of the following:

  • At least 100 colorectal adenomatous polyps (individuals at younger ages or those with colectomies may have fewer than 100 colorectal adenomatous polyps).
    Note: (1) The presence of 100 or more colorectal polyps is not specific to FAP; genetic testing of APC may help distinguish FAP from other colonic polyposis conditions (see Differential Diagnosis).
  • Multiple but fewer than 100 adenomatous polyps and a relative with confirmed FAP

The diagnosis of attenuated FAP is considered in an individual with a heterozygous germline pathogenic variant in APC by molecular genetic testing (see Table 1) and:

  • A relative with confirmed attenuated FAP; AND/OR
  • Fewer than 100 colorectal adenomatous polyps; OR
  • More than 100 colorectal adenomatous polyps at an advanced age (>40 years).

The diagnosis of gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is considered in an individual with the following [Worthley et al 2012]:

  • Gastric polyps restricted to the body and fundus
  • More than 100 polyps in the proximal stomach or more than 30 polyps in a first-degree relative of an individual with GAPPS
  • Predominantly fundic gland polyps (FGPs); some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma).
  • An autosomal dominant pattern of inheritance
  • No evidence of colorectal or duodenal polyposis

Note: (1) Other causes of gastric polyposis should be excluded, including proton pump inhibitor use (repeat endoscopy off therapy should be performed in individuals on proton pump inhibitors) and other heritable causes. (2) The above diagnostic criteria were originally proposed prior to the identification of disease-associated variants in promotor 1B of APC as the cause of GAPPS. Given this new information, disease-associated variants in promoter 1B of APC should be included in the diagnostic criteria for GAPPS, but these diagnostic criteria are rapidly evolving as more information becomes available. For example, colonic polyposis has now been seen in a select number of individuals reported to have GAPPS [Li et al 2016]

Molecular Testing

Molecular testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Testing should include both sequencing and deletion/duplication analyses of APC. Deletion/duplication testing should also include analysis of the regulatory regions (specifically promoter 1B) of APC if an APC pathogenic variant is not identified with initial testing.
  • A multigene panel that includes APC and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in APC-Associated Polyposis Conditions

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method 3
APCSequence analysis 4≤90% 5
Gene-targeted deletion/duplication analysis 6~8%-12% 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

The likelihood of detecting an APC pathogenic variant is highly dependent on the severity of colonic polyposis and on the family history. Detection rates are higher in classic polyposis than in attenuated colonic phenotypes [Sieber et al 2002, Aretz et al 2005, Michils et al 2005, Aretz et al 2006] and higher in individuals with a family history of polyposis than in those without affected family members in the previous generation [Truta et al 2005, Aretz et al 2007, Hes et al 2008]. Fewer than 30% of individuals with attenuated phenotypes are expected to have an identifiable APC pathogenic variant [Lefevre et al 2006].

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Approximately 20% of individuals with an apparent de novo APC pathogenic variant (i.e. no family history of an affected individual) have somatic mosaicism [Hes et al 2008]. In individuals with somatic mosaicism, sequencing of APC in DNA extracted from peripheral blood lymphocytes may fail to detect pathogenic variants because of weak mutation signals [Aretz et al 2007, Hes et al 2008]. This may explain (in part) the lower pathogenic variant detection rate in simplex cases (i.e., a single occurrence in a family) than in persons with an affected parent.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletion/duplication testing should also include analysis of the regulatory regions (specifically promoter 1B) of APC [Rohlin et al 2011].

7.

Approximately 8%-12% of individuals with an APC-associated polyposis condition and 100 or more polyps have a partial or whole APC deletion [Sieber et al 2002, Bunyan et al 2004, Aretz et al 2005, Michils et al 2005]. In one study, 19 (6%) of 296 individuals with ten or more adenomatous polyps who had no pathogenic variants in MUTYH (see Differential Diagnosis) or APC using sequencing, protein truncation testing, and denaturing gradient gel electrophoresis (a type of variant scanning) had a large APC deletion detected by MLPA [Nielsen et al 2007b].

Clinical Characteristics

Clinical Description

APC-associated polyposis conditions include familial adenomatous polyposis (FAP), attenuated FAP, and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).

Familial Adenomatous Polyposis (FAP)

In individuals with FAP, colorectal adenomatous polyps begin to appear in the second and third decade; the average age of polyp diagnosis is 16 years (range 7-36 years) [Petersen et al 1991]. By age 35 years, 95% of individuals with FAP have polyps. Once they appear, the polyps rapidly increase in number; when colonic expression is fully developed hundreds to thousands of colonic adenomatous polyps are typically observed. Without colectomy, colon cancer is essentially inevitable. The average age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Seven percent of untreated individuals with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years [Bussey 1975]. Although rare, asymptomatic individuals in their 50s have been reported [Evans et al 1993]. Inter- and intrafamilial phenotypic variability are common [Giardiello et al 1994, Rozen et al 1999].

Other Features Variably Present in FAP

Table 2.

Lifetime Risk for Extracolonic Cancer in FAP

SiteType of CancerLifetime Risk for Cancer
Small bowel: duodenum or periampullaCarcinoma4%-12%
Small bowel: distal to the duodenumCarcinomaRare
PancreasAdenocarcinoma~1%
ThyroidPapillary thyroid carcinoma1%-12%
CNSUsually medulloblastoma<1%
LiverHepatoblastoma1.6%
Bile ductsAdenocarcinomaLow, but increased
StomachAdenocarcinoma<1% in Western cultures

Small-bowel polyps and cancer. Adenomatous polyps of the duodenum, observed in 50%-90% of individuals with FAP, are commonly found in the second and third portions of the duodenum [Kadmon et al 2001] and less frequently in the distal small bowel [Wallace & Phillips 1998]. A classification system for duodenal polyps, based on number and size of polyps, histology, and degree of dysplasia, has been developed [Spigelman et al 1989]. No clear association between the number of colonic polyps and the number of upper gastrointestinal polyps has been identified [Kadmon et al 2001].

Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater) are seen in at least 50% of individuals with FAP. Polyps in this area can cause obstruction of the pancreatic duct resulting in pancreatitis or biliary obstruction, both of which occur at increased frequency in FAP. These polyps are often small and require a side-viewing endoscope for visualization. Some theorize that pancreaticobiliary secretions (e.g., bile) affect the development of adenomas [Wallace & Phillips 1998], and may account for the observed increased risk for malignancy of polyps in the periampullary region [Kadmon et al 2001].

The lifetime risk for small bowel malignancy is 4%-12% with the large majority occurring in the duodenum. Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [Wallace & Phillips 1998, Kadmon et al 2001]. Small-bowel cancer distal to the duodenum occurs but is rare. Ruys et al [2010] identified only 17 cases of jejunal carcinoma and three cases of ileal carcinoma in individuals with FAP reported in the literature [Ruys et al 2010].

Pancreatic cancer. Although limited data exist, one study of 197 families with FAP revealed a relative risk for pancreatic cancer of 4.5 in individuals with FAP and their at-risk relatives compared to the general population risk. The lifetime pancreatic cancer risk to age 80 in individuals with FAP was estimated at 1% [Giardiello et al 1993b].

Thyroid cancer and benign thyroid disease. A high degree of variability in the frequency of thyroid cancer is reported in individuals with FAP. Various retrospective reviews have reported a prevalence of 0.4% to 2%, whereas prospective studies have found a higher prevalence of 2.6% to 11.8% [Cetta 2015]. There is a striking female-to-male ratio of 80 to 1 in FAP and greater than 80% of individuals are diagnosed between the ages of 18 to 35 years [Cetta 2015]. Papillary histology predominates and may have a cribriform pattern [Jarrar et al 2011, Steinhagen et al 2012]. A rare subtype of papillary thyroid carcinoma, called cribriform-morular variant, is typically associated with FAP [Pradhan et al 2015]. Although it occurs in sporadic cancers, this variant of papillary thyroid carcinoma is an indication for germline APC molecular testing [NCCN 2016].

Data on the rate of benign thyroid disease in individuals with FAP are limited. In one retrospective study, 9.1% of individuals with FAP had benign thyroid disease (hypothyroidism, cysts, goiter, and/or thyroiditis) [Steinhagen et al 2012], whereas a prospective screening study found that 38% had benign thyroid nodules [Jarrar et al 2011]. Differences in sample size and study design (retrospective compared to prospective screening studies) likely contribute to the discrepancies in the rate of thyroid disease reported among studies. Familial occurrence and a female preponderance have been observed.

CNS. The CNS tumors in individuals with APC pathogenic variants are typically medulloblastoma. The risk for CNS tumors is substantially increased in persons with FAP, although the absolute risk is only approximately 1%. Historically, the combination of colonic polyposis and CNS tumors was included in the designation Turcot syndrome, but this distinction is no longer clinically useful.

Hepatoblastoma. The risk for hepatoblastoma in FAP is 750 to 7500 times higher than in the general population, although the absolute risk is estimated at less than 2% [Aretz et al 2007]. The majority of hepatoblastomas occur prior to age three years [Aretz et al 2007].

Gastric polyps and cancer. The risk for both fundic gland and adenomatous polyps of the stomach is increased in FAP [Bülow et al 1995]:

  • Gastric fundic gland polyps (FGPs) are benign neoplasms located in the fundus and body of the stomach; some authors classify them as hamartomatous, but this classification is under debate. FGPs occur in approximately half of individuals with FAP [Offerhaus et al 1999] and undergo dysplastic change more commonly than sporadic FGPs [Bianchi et al 2008]. For a complete review of gastric FGPs and their relationship to FAP and attenuated FAP, see Burt [2003].
  • Adenomatous polyps, the second most prevalent gastric lesion in individuals with FAP [Bülow et al 1995, Wallace & Phillips 1998], are usually confined to the gastric antrum [Offerhaus et al 1999].

The risk for gastric cancer in individuals with FAP living in Western cultures is low, although it has been reported [Offerhaus et al 1999, Garrean et al 2008]. The rates of gastric cancer in persons of Japanese and Korean heritage with FAP may be tenfold higher than the general population [Garrean et al 2008]. Gastric adenocarcinoma is believed to arise most often from adenomas but may also develop from fundic gland polyps [Zwick et al 1997, Hofgärtner et al 1999, Attard et al 2001].

Non-Malignant Extraintestinal Manifestations of FAP

Historically, the combination of colonic polyposis and prominent extraintestinal manifestations such as osteomas, dental abnormalities, and benign cutaneous lesions was termed Gardner’s syndrome in honor of Eldin Gardner, who originally described the association [Gardner 1951]. It is now clear that these families have a pathogenic variant in APC and should be classified as having FAP.

Osteomas occur in about 20% of individuals with FAP. They are bony growths found most commonly on the skull and mandible; however, they may occur in any bone of the body. Osteomas do not usually cause clinical problems and do not become malignant; they may appear in children prior to the development of colonic polyps.

Dental abnormalities. Unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts (an odontogenic cyst associated with the crown of an unerupted tooth), and odontomas have been reported in approximately 17% of individuals with FAP compared to 1%-2% of the general population [Brett et al 1994].

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) refers to discrete, flat, pigmented lesions of the retina that are not age dependent and do not cause clinical problems. CHRPE is reported to occur in up to 75% of individuals with FAP. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated lesions can be seen in the general population [Chen et al 2006].

Benign cutaneous lesions include epidermoid cysts and fibromas that may be found on any part of the body, including the face. They are mainly of cosmetic concern, as they do not appear to have malignant potential. Multiple pilomatricomas (benign tumors of the hair follicles), although rare, have also been reported [Pujol et al 1995].

Desmoid tumors develop in approximately 10%-30% of individuals with FAP [Nieuwenhuis et al 2011b, Sinha et al 2011]. The risk for desmoid tumors in individuals with FAP is more than 800 times the risk in the general population [Nieuwenhuis et al 2011a]. At least 7.5% of desmoid type fibromatoses are found in people with FAP [Nieuwenhuis et al 2011a]. These poorly understood, benign fibrous tumors are clonal proliferations of myofibroblasts that are locally invasive but do not metastasize [Clark et al 1999]. A pathologically distinct fibromatous lesion called a Gardner-associated fibroma (GAF) is hypothesized to be a precursor lesion [Wehrli et al 2001].

The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40 years [Sinha et al 2011]. Approximately 65% of desmoid tumors in individuals with FAP occur within the abdomen or in the abdominal wall [Sinha et al 2011]. Desmoid tumors may compress abdominal organs or complicate abdominal surgery. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors, with the highest mortality rate reported for intra-abdominal tumors [Sinha et al 2011]. Abdominal desmoid tumors may occur spontaneously or following abdominal surgery [Bertario et al 2001]. The effect of pregnancy on desmoid tumor growth or development is unknown [Sinha et al 2011]. Independent predictors for desmoid tumor development include: an APC pathogenic variant 3' of codon 1399, family history of desmoid tumors, female gender, and previous abdominal surgery [Sinha et al 2011]. Positive family history of desmoid tumor was associated with the highest magnitude of risk; having a first-degree relative with a desmoid tumor was associated with a seven-fold increase in risk [Sinha et al 2011].

Desmoid tumors are best evaluated by CT scan [Clark & Phillips 1996] or MRI. A CT scoring system for desmoid tumors in FAP has been developed [Middleton et al 2003].

Adrenal masses are reportedly two to four times more prevalent in FAP than in the general population [Rekik et al 2010]. Adrenal masses are found in 1%-3% of the general population; a retrospective analysis identified adrenal masses in 7.4% of individuals with FAP [Marchesa et al 1997], and a prospective study of 107 individuals with FAP found 13% with an adrenal mass ≥1.0 cm on abdominal CT scan [Smith et al 2000b]. Most of the masses are asymptomatic adenomas found incidentally, although functional lesions and carcinomas do occur [Marchesa et al 1997, Rekik et al 2010].

Attenuated FAP

Attenuated FAP is characterized by fewer colonic polyps (average of 30) than classic FAP but a significant risk for colorectal cancer. Polyps tend to be found more proximally in the colon than in classic FAP.

The cumulative risk for colorectal cancer by age 80 years in attenuated FAP is estimated at 70% [Neklason et al 2008]. The average age of colon cancer diagnosis in individuals with attenuated FAP is 50 to 55 years – ten to 15 years later than in those with FAP, but earlier than in those with sporadically occurring colon cancer [Spirio et al 1993, Giardiello et al 1997].

In two large kindreds with attenuated FAP and an identical APC germline pathogenic variant [Burt et al 2004, Neklason et al 2008]:

  • The median number of adenomatous polyps in 120 individuals with pathogenic variants was 25 (range 0-470);
  • Forty-four (~37%) of 120 individuals with pathogenic variants for whom detailed colonoscopy records were available had fewer than ten adenomatous polyps;
  • Three of the 44 individuals with pathogenic variants who had fewer than ten polyps had colorectal cancer; one of the three was diagnosed before age 30 years.

Additional findings in attenuated FAP can include the following:

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was first described in 2012 in three families with fundic gland polyposis and intestinal-type gastric adenocarcinoma [Worthley et al 2012]. Individuals with GAPPS in this study were reportedly at higher risk for gastric cancer than those with FAP/attenuated FAP and a normal gastric antrum, pylorus, small intestine, and colon [Worthley et al 2012]. Genetic testing of APC and other genes did not initially reveal any causative pathogenic variants in the three original families [Worthley et al 2012]. Subsequently, these three families, in addition to three new families with GAPPS, were found to have disease-associated variants in the Ying Yang 1 (YY1) binding motif of promoter 1B of APC [Li et al 2016]. The promoter 1B disease-associated variants tracked with GAPPS in all six families [Li et al 2016].

Another family with GAPPS was also found to have a YYI promoter 1B disease-associated variant in APC [Repak et al 2016]. Metastatic gastric cancer developed in one of the individuals despite endoscopic surveillance with multiple biopsies taken during each procedure [Repak et al 2016]. Two other individuals from this family underwent gastroscopies; multiple biopsies during each procedure revealed fundic gland polyposis with low-grade and focally high-grade dysplasia but no invasive cancer [Repak et al 2016]. Subsequent gastrectomy in both individuals revealed early-stage gastric adenocarcinoma (Stage IA) [Repak et al 2016].

It is thought that the reason that promoter 1B disease-associated variants result in a gastric but not colonic polyposis phenotype is that the 1B promoter drives APC expression solely in the stomach; the 1A promoter that drives APC expression in the colon is inactivated by methylation in stomach tissue. Thus, normal APC expression occurs in the colon in GAPPS via the 1A promoter but APC expression is lost in the stomach due to methylation of the 1A promoter and mutation of the 1B promoter.

Genotype-Phenotype Correlations

Although variation occurs among individuals and among and within families with identical APC pathogenic variants [Giardiello et al 1994, Friedl et al 2001], much effort has gone into making genotype-phenotype correlations. Some have suggested basing management strategies on these associations [Vasen et al 1996], whereas others feel that therapeutic decisions should not be based on genotype [Friedl et al 2001].

While not in routine use at present, the following correlations may become important in management decisions in the future (see Table 3 for reference sequences for pathogenic variants discussed in this section):

  • The most frequent APC pathogenic variant is located at codon 1309 (c.3927_3931delAAAGA) [Friedl & Aretz 2005]. Pathogenic variants at this codon lead to a high number of colonic adenomas at an early age [Friedl et al 2001, Bertario et al 2003].
  • The average age of onset in individuals with colonic symptoms [Friedl et al 2001] varied by pathogenic variant location:
    • At codon 1309: age 20 years
    • Between codon 168 and 1580 (excluding 1309): age 30 years
    • 5' of codon 168 and 3' of codon 1580: age 52 years
  • Profuse polyposis (an average of 5000 polyps) has been reported with pathogenic variants in codons 1250-1464 [Nagase et al 1992].
  • Attenuated FAP is associated with the following:
  • A fourfold increased risk for duodenal adenomas was found in individuals with pathogenic variants between codons 976 and 1067 in one study of Italian individuals with FAP [Bertario et al 2003].
  • Prominent extracolonic manifestations often correlate (though not completely) with more distal APC pathogenic variants. A retrospective study of 190 individuals with FAP that evaluated nine extracolonic manifestations (desmoid tumors, osteomas, epidermoid cysts, duodenal adenomas, gastric polyps, hepatoblastoma, dental anomalies, periampullary cancers, and brain tumors) [Wallis et al 1999] revealed that:
    • Individuals with pathogenic variants in codons 1395-1493 have significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with pathogenic variants in codons 177-452;
    • Individuals with pathogenic variants in codons 1395-1493 have significantly higher rates of desmoid tumors and osteomas than those with pathogenic variants in codons 457-1309;
    • No individuals with pathogenic variants in codons 177-452 developed osteomas or periampullary cancers;
    • Only individuals with pathogenic variants in codons 457-1309 developed hepatoblastoma and/or brain tumors.
  • Desmoid tumors also have shown the following correlations:
    • After reviewing combined data on 2098 individuals with FAP, Sinha et al [2011] found that APC pathogenic variants 3’ to codon 1399 were associated with desmoid tumor development with an odds ratio of 4.37.
    • A study of 269 individuals with identifiable APC pathogenic variants found desmoid tumors in 20% of individuals with pathogenic variants 5' to codon 1444, 49% of individuals with pathogenic variants 3' to codon 1444, and 61% of individuals with pathogenic variants in codons 1445-1580 [Friedl et al 2001].
    • Several families with severe desmoid tumors with pathogenic variants at the extreme 3' end of the gene have been reported [Eccles et al 1996, Scott et al 1996, Couture et al 2000].
    • Nieuwenhuis & Vasen [2007] revealed a consistent association of desmoid tumors with pathogenic variants distal to codon 1444.
    • The data regarding desmoid tumors and genotype associations is controversial. Church et al [2015] recently evaluated the association between incidence and severity of desmoid disease in FAP and genotype. Although a higher incidence was found with pathogenic variants 3’ of codon 1399, the authors concluded that desmoid disease can develop regardless of the APC mutation site [Church et al 2015]. Additionally, pathogenic variants in this region are more often symptomatic and lethal [Church et al 2015].
  • CHRPE is associated with:
  • In individuals with thyroid cancer and FAP:
    • In 24 individuals, the majority of pathogenic variants identified were 5' to codon 1220 [Cetta et al 2000];
    • Nine of 12 individuals had APC pathogenic variants identified proximal to the mutation cluster region (codons 1286-1513) [Truta et al 2003].
  • A review of the literature up to August 2006 and a report of additional affected individuals by Nielsen et al [2007a] revealed 89 submicroscopic APC deletions (42 partial and 47 whole-gene deletions). Most partial and whole APC deletions are associated with 100-2000 colonic adenomas, although attenuated FAP has been seen [Nielsen et al 2007a]. Extracolonic findings were seen in 36% of individuals, with no significant differences in those with partial- vs. whole-gene deletions [Nielsen et al 2007a]. One whole-gene deletion and one partial-gene deletion were found in 94 individuals with FAP [Smith et al 2016]. In six other reports of individuals with whole- or partial-gene deletions, all were classified as having a phenotype consistent with FAP as opposed to attenuated FAP [Quadri et al 2015].

Penetrance

In FAP, the penetrance of colonic adenomatous polyposis and colon cancer is virtually 100% in untreated individuals.

In attenuated FAP, the penetrance of colonic polyposis is less well understood, although the estimate of colon cancer risk by age 80 years is approximately 70% [Neklason et al 2008].

In GAPPS, the penetrance of gastrointestinal polyps and cancer is currently unknown.

See Clinical Description for discussion of penetrance of other intestinal and extraintestinal manifestations in APC-associated polyposis conditions.

Nomenclature

FAP is also known as familial polyposis coli. A term used historically for FAP is adenomatous polyposis coli (i.e., APC); APC now refers to the relevant gene. FAP is often referred to as classic FAP when more than 100 colorectal polyps are present. Classic FAP and FAP may be used interchangeably.

Gardner syndrome is the association of colonic adenomatous polyposis of FAP with osteomas and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953]. When these findings are prominent, many clinicians continue to use the term Gardner syndrome. However, they can occur in any individual with FAP, whether or not other extraintestinal findings are present. Gardner syndrome was once thought to be a distinct clinical entity; however, it is now known that pathogenic variants in APC give rise to both FAP and Gardner syndrome. Other manifestations of FAP (e.g., upper gastrointestinal polyposis) are also found in Gardner syndrome. Some correlation exists between extraintestinal growths and pathogenic variant location in APC. See Genotype-Phenotype Correlations.

Turcot syndrome is the association of colonic polyposis or colorectal cancer and central nervous system (CNS) tumors. Historically, Turcot syndrome was used to describe individuals with either FAP or Lynch syndrome (see Differential Diagnosis) who also had CNS tumors. The molecular basis of Turcot syndrome is either an APC pathogenic variant associated with FAP or a pathogenic variant in one of the genes associated with Lynch syndrome [Hamilton et al 1995]. The CNS tumors in individuals with APC pathogenic variants are typically medulloblastoma, whereas those with Lynch syndrome are usually glioblastoma multiforme. Like Gardner syndrome, Turcot syndrome was once thought to be a distinct clinical entity; however, it is now assumed that all individuals with FAP are at increased risk for brain tumors, albeit a relatively low lifetime risk. Thus, Turcot syndrome is a historical term of little clinical utility.

Attenuated FAP (also referred to as attenuated adenomatous polyposis coli) appears to be the same as the “hereditary flat adenoma syndrome” [Lynch et al 1992].

Prevalence

Estimates of the prevalence of FAP vary from 1:6,850 to 1:31,250 live births (2.29 to 3.2 cases per 100,000 individuals) [Bussey 1975, Järvinen 1992, Bisgaard et al 1994, Bülow et al 1996, Björk et al 1999, Iwama et al 2004, Scheuner et al 2010]. The frequency is fairly constant throughout the world, with men and women being affected equally.

Attenuated FAP is likely underdiagnosed, given the lower number of colonic polyps and lower risk for colorectal cancer compared to FAP [Neklason et al 2008].

The prevalence of GAPPS is currently unknown.

APC-associated polyposis conditions historically accounted for about 0.5% of all colorectal cancers; this figure is declining as more at-risk family members undergo successful treatment following early polyp detection and prophylactic colectomy.

Differential Diagnosis

APC-associated polyposis conditions may be distinguished from other inherited colon cancer conditions and other gastrointestinal polyposis syndromes by molecular genetic testing, histopathologic findings, and phenotypic characteristics.

Hereditary Disorders to Consider in the Differential Diagnosis

MUTYH-associated polyposis (MAP). The colonic phenotype of MAP can be similar to attenuated FAP but is inherited in an autosomal recessive manner. Germline biallelic pathogenic variants in MUTYH predispose individuals to multiple adenoma or polyposis coli. If an APC pathogenic variant is not identified in an individual with colonic polyposis, molecular genetic testing of MUTYH should be considered [Sieber et al 2003].

Biallelic MUTYH pathogenic variants have been found in a few individuals diagnosed with colorectal cancer at age 50 years or younger who have had few or no polyps [Wang et al 2004]. The frequency of duodenal polyposis is between 4% and 25% among individuals with biallelic MUTYH pathogenic variants; extraintestinal findings are also noted on occasion [Aretz et al 2006].

In one study of individuals with polyposis without an identified APC pathogenic variant, the detection rate of MUTYH pathogenic variants varied by the colonic severity [Aretz et al 2006]; biallelic MUTYH pathogenic variants were found in:

  • Forty (18%) of 227 individuals diagnosed with ten to 100 polyps after age 25 years or more than 100 polyps after age 45 years;
  • Seven (27%) of 26 individuals with more than 100 polyps diagnosed between ages 35 and 45 years;
  • None of 41 individuals with more than 100 polyps diagnosed before 35 years of age;
  • One individual with approximately 1,000 polyps diagnosed at age 68 years.

Lynch syndrome (hereditary non-polyposis colon cancer, HNPCC) is caused by a heterozygous germline pathogenic variant in one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM. Lynch syndrome is characterized by an increased risk for colorectal cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin). It may be difficult to distinguish between Lynch syndrome and attenuated FAP in individuals with early-onset colorectal cancer and few adenomatous colonic polyps [Cao et al 2002]. In this situation, family history of extracolonic cancers and manifestations as well as microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) testing on a tumor block from a cancer may be helpful in deciding which condition is more likely.

Biallelic pathogenic variants in the mismatch repair genes, although rare, have been reported. Affected individuals frequently have brain tumors, hematologic malignancies, and/or colorectal or other Lynch syndrome cancers in childhood [de Vos et al 2005, Felton et al 2007]. Café-au-lait macules and/or axillary/inguinal freckling are seen in most individuals, and multiple colorectal adenomas mimicking attenuated FAP may also be present [Felton et al 2007, Jasperson et al 2011].

MSH3-associated polyposis, caused by biallelic pathogenic variants in the DNA mismatch repair gene MSH3, is inherited in an autosomal recessive manner. It is characterized by colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and early-onset astrocytoma [Adam et al 2016].

Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal Peutz-Jeghers type polyps and mucocutaneous pigmentation, neither of which are present in APC-associated polyposis conditions. PJS polyps are often symptomatic and most prevalent in the small intestine (jejunum, ileum, and duodenum in order of prevalence) but can occur elsewhere in the gastrointestinal tract. PJS is inherited in an autosomal dominant manner. Molecular genetic testing of STK11 reveals pathogenic variants in most individuals.

PTEN hamartoma tumor syndrome (PHTS). Cowden syndrome (CS), the most common presentation of PHTS, is associated with multiple colorectal polyps, although unlike in APC-associated polyposis conditions, hamartomatous polyps, juvenile polyps, lipomas, and ganglioneuromas predominate; an increased risk of colon cancer is found in Cowden syndrome; however, breast, thyroid, and endometrial cancer are more common. Approximately 80% of individuals who meet the diagnostic criteria for CS have a detectable PTEN pathogenic variant.

Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps, which is often the distinguishing feature between the APC-associated polyposis conditions and JPS. The hamartomatous polyps occur in the GI tract – specifically in the stomach, small intestine, colon, and rectum. Most individuals with JPS have some polyps by age 20 years. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. Most juvenile polyps are benign; however, malignant transformation can occur. JPS is inherited in an autosomal dominant manner. Approximately 20% of individuals with JPS have SMAD4 pathogenic variants, while 20% have BMPR1A pathogenic variants; none have been found to have APC pathogenic variants.

Hereditary mixed polyposis syndrome (HMPS) is associated with an increased risk for colorectal cancer and multiple different types of colorectal polyps (OMIM 601228). The characteristic lesions in HMPS are mixed juvenile-adenomatous colon polyps [Rozen et al 2003]. Additionally, adenomas, hyperplastic serrated adenomas, and mixed hyperplastic-adenomatous polyps may occur. HMPS is caused by a duplication upstream of GREM1 [Jaeger et al 2012].

Neurofibromatosis type 1 (NF1). Individuals with NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in the small bowel, stomach, and colon. NF1 is caused by pathogenic variants in NF1 and is inherited in an autosomal dominant manner.

NTHL1-associated polyposis (OMIM 616415), caused by biallelic germline NTHL1 pathogenic variants, is inherited in an autosomal recessive manner. Seven affected individuals with adenomatous polyposis (range 8-50 polyps) from three unrelated families were originally reported [Weren et al 2015]. Four of these individuals were diagnosed with colorectal cancer (age range 40-67 years), each of them having multiple colorectal tumors. Individuals with NTHL1-associated polyposis may also be at increased risk for endometrial cancer, premalignant endometrial lesions, duodenal adenomas, and duodenal cancer [Weren et al 2015]. Multiple primary tumors (colon cancer, mixed mucinous and serous ovarian cysts, intradermal nevi, bladder carcinoma, meningioma, multiple seborrheic keratosis, basal-cell carcinoma, multiple colorectal adenomas, squamous-cell carcinoma, and invasive breast cancer) were also documented in another individual found to have biallelic germline NTHL1 pathogenic variants [Rivera et al 2015].

Acquired Conditions to be Considered in the Differential Diagnosis

Cronkhite-Canada syndrome is characterized by generalized gastrointestinal hamartomatous polyposis, cutaneous hyperpigmentation, hair loss, and nail atrophy.

Nodular lymphoid hyperplasia, a lymphoproliferative disorder resulting in hyperplastic lymphoid nodules in small bowel, stomach, and colon, may be associated with common variable immunodeficiency syndrome.

Lymphomatous polyposis is characterized by occurrence of primary extranodal lymphomas in the gastrointestinal tract. Two types include multiple lymphomatous polyposis and Mediterranean-type lymphoma.

Inflammatory polyposis is characterized by acquired, non-neoplastic polyps associated with inflammatory bowel disease, most commonly ulcerative colitis.

Sporadic colorectal tumors. The majority of colorectal tumors not known to be familial have been associated with a somatic pathogenic variant in APC [Miyoshi et al 1992, Powell et al 1992, Smith et al 1993] that is believed to occur early in colorectal tumorigenesis [Fearon & Vogelstein 1990].

Therapy-associated polyposis was recently reported as a possible cause of gastrointestinal polyposis [Yurgelun et al 2014]. Five childhood cancer survivors, all treated with radiotherapy and chemotherapy, were reported to have gastrointestinal polyposis [Yurgelun et al 2014]. However, it is unclear whether the chemotherapy/radiation was causative of the gastrointestinal polyposis or coincidentally present in these five individuals.

Other

Serrated polyposis syndrome (previously termed hyperplastic polyposis), comprises multiple colorectal serrated polyps (hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas). It is unknown whether this condition is inherited or acquired [Snover et al 2010]. Although serrated polyps typically predominate, individuals with serrated polyposis frequently have multiple colorectal adenomas as well [Kalady et al 2011]. Individuals with serrated polyposis syndrome may also have a family history of colorectal cancer, although it is uncommon for more than one member of a family to meet the diagnostic criteria for serrated polyposis syndrome.

Management

Evaluations Following Initial Diagnosis

Individuals who are diagnosed with FAP or attenuated FAP should be counseled about age-appropriate recommendations for surveillance and prevention of primary manifestations, in addition to treatment of manifestations, as outlined in this section. Currently, consensus management guidelines for GAPPS are unavailable.

Treatment of Manifestations

Practice parameters, including information on surgery, have been outlined by the National Comprehensive Cancer Network (NCCN) [Provenzale et al 2016] (full text), the American College of Gastroenterology [Syngal et al 2015] (full text), the American Society of Colon and Rectal Surgeons [Church et al 2003b], the American Society of Clinical Oncology [Stoffel et al 2015] (full text), and the Society of Surgical Oncology [Guillem et al 2006] (full text).

Colonic polyps. For individuals with FAP, colectomy is recommended after adenomas emerge. Colectomy may be delayed depending on adenoma size, presence of advanced histology (villous architecture, high-grade dysplasia), and number of adenomatous polyps. Absolute indications for colectomy include documented or suspected colorectal cancer or significant symptoms (obstruction, bleeding – although these are uncommon in the absence of cancer). Relative indications for colectomy include presence of multiple adenomas larger than 6 mm that cannot be reasonably managed by endoscopy, a significant increase in adenoma number between surveillance examinations, presence of adenomas with high-grade dysplasia or inability to adequately survey the colon (e.g., due to innumerous diminutive adenomas or limited access/compliance with colonoscopy).

For individuals with attenuated FAP, colectomy may be necessary, but in approximately one third of individuals the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient (see Surveillance).

Types of colectomy include the following:

  • Proctocolectomy with ileal pouch anal anastomosis (IPAA) which can be performed laparoscopically, laparoscopically-assisted, or open. The IPAA can be stapled, leaving 1-2 cm of anal transition epithelium and low rectal mucosa; or it can be hand-sewn after a complete anal mucosectomy.
  • Total colectomy with ileorectal anastomosis (IRA). This is a single-stage procedure.
  • Total proctocolectomy with permanent ileostomy

The choice of procedure depends on the clinical circumstances.

  • An IPAA is generally performed in FAP where the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantage of this procedure is nearly eliminating the risk of rectal cancer and relatively good preservation of bowel function. There may be an increased risk of bladder/sexual dysfunction and functional results can be variable.
    A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch. No apparent relationship between the development of pouch adenomas and the severity of polyps in the colon or duodenum was found [Groves et al 2005]. Cancer in the surgical transition zone has been reported [Ooi et al 2003] but is rare.
  • An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable (usually in the setting of attenuated FAP). It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk of sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum post-operatively.
  • A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).

Small-bowel polyps. Endoscopic or surgical removal of duodenal and/or ampullary adenomas is recommended if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms [Wallace & Phillips 1998, Saurin et al 1999, Kadmon et al 2001].

Surgical options include a pancreas-sparing duodenectomy which is a good option when the papilla is not involved and there is no suspicion for cancer. Pancreaticoduodenectomy (Whipple procedure) is a surgical option associated with significantly higher morbidity; however, it must be considered if the duodenal papilla is involved or there is confirmed or strongly suspected cancer.

Osteomas may be removed for cosmetic reasons.

Desmoid tumors. Available treatments include surgical excision (associated with high rates of recurrence), nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation [Griffioen et al 1998, Clark et al 1999, Smith et al 2000a, Tonelli et al 2003, Gega et al 2006]. A review of desmoid treatments can be found in Guillem et al [2006].

Adrenal tumors. Smith et al [2000b] and Ferrández et al [2006] found no evidence to warrant screening for adrenal masses in FAP.

Chemoprevention. There are currently no FDA-approved chemopreventive agents for FAP.

NSAIDs. Non-placebo controlled trials and observational studies on sulindac were initially promising, showing remarkable reduction in polyp size and number.. However, these preliminary studies were limited in their design (non-placebo controlled, limited number of affected individuals, some individuals with only surveyable rectum). Several controlled trials subsequently confirmed a decrease in polyp burden during sulindac therapy [Labayle et al 1991, Giardiello et al 1993a, Nugent et al 1993]. Rapid reappearance or increase in polyp number was observed, however, after sulindac was stopped [Labayle et al 1991, Giardiello et al 1993a]. A subsequent study designed to evaluate primary prevention of polyps in indivduals with APC pathogenic variants showed a non-statistically significant trend towards benefit compared to placebo [Giardiello et al 2002].

The FDA initially approved celecoxib for FAP based on evidence showing decrease in polyp burden and size in the colon (as well as modest decrease in the duodenum) [Steinbach et al 2000, Phillips et al 2002]. However, due to cardiovascular and cerebrovascular safety concerns, rofecoxib was taken off the market altogether and FDA approval for celecoxib for FAP was withdrawn.

Aspirin has been shown to be of little or no benefit in FAP [Burn et al 2011, Ishikawa et al 2013].

Interest in combination of NSAIDs with other drugs was raised when reports of sulindac plus difluoromethylornithine (celecoxib) showed marked reduction in sporadic metachronous adenomas [Meyskens et al 2008]. In a randomized placebo-controlled study of 92 participants with FAP, sulindac plus erlotinib (an EGF receptor inhibitor) resulted in decreased duodenal polyp burden compared to placebo after six months of use [Samadder et al 2016]. Adverse events were common in the treatment group (87% experienced an acne-like rash), though serious adverse events were rare (2 total participants) [Samadder et al 2016]. When celecoxib was compared to celecoxib plus difluoromethylornithine (DFMO) in FAP, there was no significant difference in polyp burden within a defined endoscopic field (however, when more comprehensive video assessment was used, there was a decrease in polyp burden in the combination therapy group) [Lynch et al 2016].

A number of chemoprevention trials are currently under way (see Therapies Under Investigation). The FDA has stated that changes in adenoma number and size are insufficient for regulatory approval, with evidence of clinical benefit required. Suitable examples of clinical benefit cited include decreasing the risk of colorectal cancer or reducing the need for surgery. Trials currently under way are designed to address these end points.

Note: NSAID use before colectomy remains experimental (see Therapies Under Investigation).

Prevention of Primary Manifestations

Colectomy is advised to reduce the risk for colorectal cancer in FAP. For individuals with attenuated FAP, colectomy may be necessary, but in approximately one third of individuals, the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient to prevent colorectal cancer. Colonoscopy can therefore be utilized for surveillance, as well as prevention of colorectal cancer.

To reduce the risk for duodenal/periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms.

Surveillance

Multiple professional societies have published guidelines based on the available evidence to date as well as expert consensus [Church et al 2003b, Syngal et al 2015, NCCN 2016]. The following surveillance recommendations are based on these expert society guidelines.

In individuals known to have FAP

  • Sigmoidoscopy or colonoscopy every one to two years, beginning at age ten to 12 years
  • Colonoscopy, once polyps are detected
  • Annual colonoscopy thereafter if colectomy is delayed more than a year after polyps emerge. In individuals age ten to 20 years in whom adenomas are smaller than 6.0 mm and without villous component or high grade dysplasia, delay in colectomy may be considered.
  • Esophagogastroduodenoscopy (EGD) including complete visualization of the ampulla of Vater (using a duodenoscope if necessary) is recommended, though the age of initiation is variable. The American College of Gastroenterology recommends beginning screening at age 23 to 30 years, whereas the NCCN recommends starting at age 20 to 25 years or prior to colectomy. Surveillance is recommended every six months to four years depending on duodenal adenoma burden. The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency. The Spigelman staging criteria are summarized by Syngal et al [2015] (see Table 9). The NCCN recommends examination of the stomach at time of upper endoscopy (frequency determined by duodenal polyp surveillance). Fundic gland polyps are common in FAP and low-grade dysplasia can be found, but rarely progresses. Specific gastric polyp screening or surgery should be considered in the setting of high-grade dysplasia only. Non-fundic gland polyps should be removed endoscopically.
  • Annual physical examination including evaluation for extraintestinal manifestations and neurologic deficits (to screen for CNS neoplasm) and palpation of the thyroid starting in the late teenage years
  • Thyroid cancer. In addition to annual thyroid examination, starting in late teenage years [NCCN 2016], annual thyroid ultrasound may be considered with fine-needle aspiration if thyroid nodules are present [Herraiz et al 2007]. Thyroid screening with ultrasound, even without clinical findings, may also be warranted, as none of the five affected individuals with thyroid cancer in one study were detected with neck examination [Jarrar et al 2011]; however, data supporting this recommendation are limited [NCCN 2016].
  • Annual abdominal palpation for desmoids. If family history of desmoids, consider MRI or CT scan within one to three years post colectomy and then every five to ten years. Data to support screening and treatment of desmoid tumors are limited.
  • Small-bowel polyps and cancer. Although the American College of Gastroenterology [Syngal et al 2015] does not recommend routine small bowel screening distal to the duodenum, the NCCN recommends considering adding small bowel visualization to CT or MRI for desmoids (if applicable), especially if duodenal polyposis is advanced.
  • Screening for hepatoblastoma. Efficacy in individuals with FAP is unclear. Screening protocols in Beckwith-Wiedemann syndrome, in which the risk for hepatoblastoma is also increased, often include frequent (every 2-3 months) abdominal ultrasound examinations and measurement of serum alpha-fetoprotein (AFP) concentrations, and have resulted in early detection of hepatoblastomas [Tan & Amor 2006]. Screening for hepatoblastoma in FAP using liver palpation, abdominal ultrasound, and measurement of AFP every three to six months during the first five years of life has been suggested [NCCN 2016].
  • Adrenal tumors. Smith et al [2000b] and Ferrández et al [2006] found no evidence to warrant screening for adrenal masses in FAP.

In individuals who have undergone colectomy

  • If total colectomy with IPAA is performed, routine endoscopic surveillance of the ileal pouch is recommended every two years [Syngal et al 2015, NCCN 2016].
  • If subtotal colectomy with ileorectal anastomosis is performed, surveillance of the remaining rectum every six to 12 months, depending on the number of polyps that develop [Syngal et al 2015, NCCN 2016]. Cancer may still occur in the remaining rectum, but the risk is low with current management [Church et al 2003a].
  • If total colectomy with end ileostomy is performed, ileoscopy is recommended every two years [NCCN 2016].

In individuals known to have attenuated FAP

  • Colonoscopy every two to three years, beginning in late teens
  • Once adenomas are detected, colonoscopy with polypectomy every one to two years depending on polyp burden
  • Colectomy. The absolute and relative indications for colectomy are the same as for FAP (see Surveillance).
  • Screening and surveillance of the upper gastrointestinal tract as for FAP (see Surveillance)
  • Annual physical examination, including evaluation for extraintestinal manifestations, neurologic deficits (to screen for CNS neoplasm), and palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present [Herraiz et al 2007]. Thyroid screening with ultrasound, even without clinical findings, may also be warranted, as none of the five affected individuals with thyroid cancer in one study were detected with neck examination [Jarrar et al 2011].
  • Due to the lower risk of desmoid tumors and hepatoblastomas in attenuated FAP compared to FAP, screening of these tumors is currently not recommended.

In individuals known to have GAPPS. It is currently unknown if screening for gastric cancer or prophylactic gastrectomy should be considered in individuals with GAPPS. Due to the extent of gastric polyposis, in addition to reports of rapid progression of fundic gland polyposis, gastric cancer surveillance in this condition may have limited effectiveness [Repak et al 2016].

Agents/Circumstances to Avoid

Surgery and desmoid risk. There is evidence that the risk for desmoid tumors is increased by abdominal surgery and may be higher in surgical procedures that require two stages to complete. Individuals at high risk for desmoids (women; those with APC pathogenic variants in codons 1395-1493; those with a family history of desmoids) may consider delaying surgery longer than might otherwise be recommended or undergoing an operation that is likely to be definitive for colorectal cancer risk (e.g., total colectomy with ileostomy) in order to minimize the likelihood of the need for a second operation.

Surgery and fecundity. There is a lower rate of fecundity in women after a total colectomy with ileo-anal anastamosis than after an ileorectal anastamosis. This issue should be included as part of the discussion of surgical options with women with FAP [Olsen et al 2003].

Evaluation of Relatives at Risk

Recommended genetic testing for at-risk family members. Early recognition of APC-associated polyposis conditions may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic at-risk children for early manifestations is appropriate; see Syngal et al [2015] (full text), NCCN [2016].

Use of molecular genetic testing for early identification of at-risk family members (see Genetic Counseling) improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant. A cost analysis comparing molecular genetic testing and sigmoidoscopy screening for individuals at risk for APC-associated polyposis conditions shows that genetic testing is more cost effective than sigmoidoscopy in determining who in the family is affected [Cromwell et al 1998]. Additionally, individuals diagnosed with APC-associated polyposis conditions as a result of having an affected relative have a significantly greater life expectancy than those individuals diagnosed on the basis of symptoms [Heiskanen et al 2000].

As colon screening for those at risk for FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring. Colon screening for those with attenuated FAP begins in late teenage years; thus, molecular genetic testing may be delayed until that time.

Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or the needs of the parents and/or child.

Pregnancy Management

Pregnancy/fertility/hormone use. Limited information is available on the effect of pregnancy on females with FAP. In one study of 58 Danish women with FAP including 16 who had undergone colonic surgery, the same frequency of fertility, pregnancy, and delivery was observed as in a control population [Johansen et al 1990]. A larger study of 162 women with FAP compared fertility rates before and after two types of colorectal surgery with a control population. Women with FAP who had not yet undergone surgery had the same fertility as a control population of normal women. Additionally, those women with FAP who had a colectomy with ileorectal anastomosis (IRA) had the same fertility as the control population. Fertility was significantly reduced in women with FAP who had a proctocolectomy with ileal pouch-anal anastomosis (IPAA) compared to the control population [Olsen et al 2003].

In another study, the prevalence of self-reported fertility problems was similar among individuals with FAP who had undergone IRA, IPAA, or proctocolectomy with ileostomy [Nieuwenhuis et al 2010]. However, those who had their first surgical procedure at a younger age had more postoperative fertility problems [Nieuwenhuis et al 2010].

Little evidence supports an association between desmoid tumor development or growth and pregnancy [Sinha et al 2011].

Women who have undergone colectomy are considered to be at the same risk for obstetric complications as any other woman who has had major abdominal surgery and are more likely to be delivered by C-section than those without such surgery.

As anti-estrogen medications have been successfully used in the treatment of desmoid tumors, the development of desmoid tumors is thought to be affected by hormones important in pregnancy. However, one study has shown that women who had a previous pregnancy and developed a desmoid tumor had significantly fewer complications from the desmoid tumor than those who had never had a pregnancy [Church & McGannon 2000].

In a study of women with FAP at the time of their colectomy, no association was found between pregnancy history and colonic polyp severity; however, the proportion of parous women with severe duodenal disease was significantly higher than the proportion of nulliparous women [Suraweera et al 2007].

Some studies have suggested that female hormones protect against colorectal cancer development in the general population. In one woman, reduction in polyps after use of oral contraceptives was observed [Giardiello et al 2005].

Therapies Under Investigation

There is currently an ongoing (recruitment is complete) multicenter trial comparing DFMO plus sulindac versus each agent alone to evaluate time to first occurrence of an FAP-related event (defined as need for surgery or development of advanced neoplasia or death). See ClinicalTrials.

In a single controlled trial, the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) led to a 20%-30% decrease in FAP polyp size and number [West et al 2010]. Trials with similar agents are being planned.

Curcumin is the main component in the spice turmeric. In a small uncontrolled series of five affected individuals, all individuals had a reduction in polyp size and number after six months of therapy compared to baseline [Cruz-Correa et al 2006]. Recruitment has been completed on a 12-month dual-center, double-blinded randomized placebo-controlled trial of curcumin in FAP with a primary outcome of polyp size and number. See ClinicalTrials.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

APC-associated polyposis conditions are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The majority of individuals diagnosed with an APC-associated polyposis condition have an affected parent.
  • Approximately 20%-25% of individuals with FAP, have a de novo pathogenic variant [Bisgaard et al 1994].
  • It is appropriate to evaluate the parents of an affected individual: (a) with molecular genetic testing of APC if the pathogenic variant is known in the proband; or (b) for clinical manifestations of APC-associated polyposis conditions if genetic testing cannot be performed in the proband.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported in several families [Hes et al 2008, Schwab et al 2008, Spier et al 2016].
  • Although most individuals diagnosed with an APC-associated polyposis condition have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

Offspring of a proband. Each child of an individual with an APC-associated polyposis condition has a 50% chance of inheriting the APC pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected or has an APC pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic individuals. Consideration of molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management, Evaluation of Relatives at Risk).

Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members when a clinically diagnosed relative has undergone molecular genetic testing and is found to have a pathogenic variant in APC.

The use of molecular genetic testing for determining the genetic status of at-risk relatives when a clinically diagnosed relative is not available for testing is problematic, and test results need to be interpreted with caution. A positive test result in the at-risk family member indicates the presence of an APC pathogenic variant and also indicates that the same molecular genetic testing method can be used to assess the genetic status of other, at-risk family members. In contrast, when genetic testing is offered to an at-risk family member prior to testing a family member known to be affected, the failure to identify a pathogenic variant in the at-risk family member does not eliminate the possibility that an APC pathogenic variant is present in other members of the family.

Because colon screening for those at risk for FAP begins as early as age ten years, molecular genetic testing is generally offered to individuals by this age. Colon screening for those at risk for attenuated FAP begins at age 18 to 20 years; thus, molecular genetic testing should be offered at about age 18 years.

Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. Although most children do not show evidence of clinically significant psychological problems after presymptomatic testing, Codori et al [2003] recommend that long-term psychological support be available to these families.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling - for health professionals (part of PDQ®, National Cancer Institute).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo or due to parental mosaicism as described in Risk to Family Members. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the APC pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible [Rechitsky et al 2002, Davis et al 2006, Moutou et al 2007]. The criteria for use of molecular genetic testing discussed in Related Genetic Counseling Issues, Testing of at-risk asymptomatic individuals apply to prenatal testing as well. It should be noted that detection of an APC pathogenic variant in a fetus at risk does not predict the time of onset or severity of the disease.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA)
  • Familial Adenomatous Polyposis Foundation
    P.O. Box 2005
    Park City UT 84060
    Phone: 334-740-8657
    Email: info@fapfoundation.org
  • Hereditary Colon Cancer Takes Guts
  • My46 Trait Profile
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Library of Medicine Genetics Home Reference
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • C3: Colorectal Cancer Coalition
    1414 Prince Street
    Suite 204
    Alexandria VA 22314
    Phone: 877-427-2111 (toll-free); 703-548-1225
    Fax: 202-315-3871
    Email: info@fightcolorectalcancer.org
  • Colon Cancer Alliance (CCA)
    1200 G Street Northwest
    Suite 800
    Washington DC 20005
    Phone: 877-422-2030 (Toll-free Helpline); 202-434-8980
    Fax: 866-304-9075 (toll-free)
  • Desmoid Tumor Research Foundation (DTRF)
    P.O. Box 273
    Suffern NY 10901
    Email: marlene@dtrf.org
  • United Ostomy Associations of America, Inc. (UOAA)
    PO Box 66
    Fairview TN 37062-0066
    Phone: 800-826-0826 (toll-free)
    Email: info@uoaa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

APC-Associated Polyposis Conditions: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for APC-Associated Polyposis Conditions (View All in OMIM)

175100FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1
611731APC GENE; APC

Gene structure. APC is alternatively spliced in multiple coding and non-coding regions; the primary transcript NM_000038.5 has 15 coding exons that code for 2843 amino acids and result in a 311.8-kd protein. The last coding exon is large and comprises more than three quarters of the coding region of the gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. At least 700 germline pathogenic variants have been found in families with an APC-associated polyposis condition [Béroud et al 2000]. Pathogenic variants almost always cause a premature truncation of the APC protein, usually through single amino-acid substitutions or frameshifts. While pathogenic variants have been found scattered throughout the gene, they are predominantly located in the 5' end of the gene. The most common germline APC pathogenic variant is c.3927_3931delAAAGA. (For more information, see Table A.)

Table 3.

Selected APC Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.3927_3931delAAAGAp.Glu1309AspfsTer4NM_000038​.5
NP_000029​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The APC protein has been localized to the nucleus and membrane/cytoskeleton in human epithelial cells [Neufeld & White 1997]. It has also been shown to homodimerize [Joslyn et al 1993] and bind to other proteins including GSK3b [Rubinfeld et al 1996], beta-catenin [Rubinfeld et al 1993, Su et al 1993], gamma-catenin [Hülsken et al 1994, Rubinfeld et al 1995], tubulin [Munemitsu et al 1994, Smith et al 1994], EB1 [Su et al 1995], and hDLG, a homolog of the Drosophila discs large tumor-suppressor protein [Matsumine et al 1996]. The APC protein product is a tumor suppressor. APC protein forms a complex with glycogen synthase kinase 3b (GSK-3b) [Rubinfeld et al 1996]; the complex functions to target cytosolic beta-catenin for phosphorylations and subsequent ubiquitin-mediated proteosomal destruction. Beta-catenin is a protein involved in both cell adhesion and intracellular signal transduction [Korinek et al 1997, Morin et al 1997, Nakamura 1997, Peifer 1997, Rubinfeld et al 1997]. The presence of normal APC protein appears to prevent accumulation of cytosolic beta-catenin and maintain normal apoptosis and may also decrease cell proliferation, probably through its regulation of beta-catenin. This pathway is normally involved with Wingless-Wnt signaling, which participates in several known cell growth functions [Krausova & Korinek 2014].

The APC protein has also been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome segregation in mouse embryonic stem cells [Fodde et al 2001, Kaplan et al 2001]. The APC protein may play a role in chromosome instability, the presence of which is often observed when APC function is lost.

Other possible roles for the APC protein include: regulation of cell migration up the colonic crypt and cell adhesion through association with E-cadherin, regulation of cell polarity through association with GSK3b, and other functions related to association with microtubule bundles [Näthke et al 1996, Barth et al 1997, Etienne-Manneville & Hall 2003]. Goss & Groden [2000] provide an excellent review of the function of the APC protein.

Abnormal gene product. Pathogenic variants in APC most often result in truncated protein products. Experiments have localized normal full-length APC protein to the membrane/cytoskeleton and nuclear fractions of human epithelial cells but demonstrated that colon cancer cells containing only mutated APC alleles revealed no truncated APC protein in nuclear fractions [Neufeld & White 1997].

Pathogenic APC variants produce an abnormal (usually truncated) protein that can no longer bind to GSK-3b and does not target beta-catenin for destruction, resulting in high levels of free cytosolic beta-catenin. Free beta-catenin migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate expression of genes such as the oncogenes c-Myc and cyclin D1 [Chung 2000]. All targets of APC are not yet known but may include those increasing proliferation or decreasing apoptosis. Because APC may be important in cell migration, abnormal APC protein may also disrupt normal cellular positioning in the colonic crypt. Additionally, pathogenic variants in APC are thought to contribute to chromosome instability in colorectal cancers [Fodde et al 2001].

References

Published Guidelines/Consensus Statements

  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. [PubMed: 12692171]
  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
  • Burt RW, Cannon JA, David DS, Early DS, Ford JM, Giardiello FM, Halverson AL, Hamilton SR, Hampel H, Ismail MK, Jasperson K, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Ness RM, Provenzale D, Rao MS, Shike M, Steinbach G, Terdiman JP, Weinberg D, Dwyer M, Freedman-Cass D. Colorectal cancer screening. Available online. 2013. Accessed 2-28-18.
  • Church J, Simmang C. Standards Task Force; American Society of Colon and Rectal Surgeons; Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of The American Society of Colon and Rectal Surgeons. American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003;46:1001–12. [PubMed: 12907889]
  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-28-18. [PubMed: 23428972]
  • Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. 2001. [PubMed: 11438509]
  • Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL, Giardiello F, Rodriguez-Bigas MA, Church J, Gruber S, Offit K. American Society of Clinical Oncology/Society of Surgical Oncology review of current role of risk-reducing surgery in common hereditary cancer syndromes. Available online. 2006. Accessed 2-28-18. [PubMed: 17008706]
  • Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). American College of Medical Genetics. Available online. 2014. Accessed 2-28-18. [PubMed: 24310308]
  • NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. 2016.
  • Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. American College of Gastroenterology. Available online. 2015. Accessed 2-28-18.
  • Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucii J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C for the US Multisociety Task Force on Colorectal Cancer. Colorectal cancer screening and surveillance: clinical guidelines and rationale - Update based on new evidence. American Gastroenterological Association. 2003. [PubMed: 12557158]

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Suggested Reading

  • Bunz F, Kinzler KW, Vogelstein B. Colorectal tumors. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 48. McGraw-Hill.
  • Olschwang S. Familial adenomatous polyposis (FAP). Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 1998.

Chapter Notes

Author History

Dennis J Ahnen, MD (2017-present)
Randall W Burt, MD; Huntsman Cancer Institute (1998-2017)
Kory W Jasperson, MS (2008-present)
Swati G Patel, MD, MS (2017-present)
Cindy Solomon, MS; Myriad Genetic Laboratories (1998-2008)

Revision History

  • 2 February 2017 (sw) Comprehensive update posted live
  • 27 March 2014 (me) Comprehensive update posted live
  • 27 October 2011 (me) Comprehensive update posted live
  • 24 July 2008 (me) Comprehensive update posted live
  • 21 October 2005 (me) Comprehensive update posted live
  • 20 September 2004 (chs) Revision: new clinical method
  • 27 May 2004 (chs) Revision: Genetic Counseling - genetic cancer subsection added
  • 15 March 2004 (me) Comprehensive update posted live
  • 23 June 2003 (cd) Revision: terminology
  • 18 January 2002 (me) Comprehensive update posted live
  • 18 December 1998 (pb) Review posted live
  • 11 September 1998 (ch) Original submission
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